Plakophilin3 loss leads to an increase in autophagy and radio-resistance.

Loss of the desmosomal plaque protein plakophilin3 (PKP3) leads to increased tumor progression and metastasis. As metastatic tumors are often resistant to therapy, we wished to determine whether PKP3 loss led to increased radioresistance. PKP3 knockdown cells showed increased resistance to radiation in vitro and in vivo. The increase in resistance was accompanied by an increased ability to clear reactive oxygen species (ROS) and increased autophagy. The increase in autophagy was required for radioresistance and ROS clearance as inhibiting autophagy using either chloroquine or knocking down ATG3 re-sensitized the PKP3 knockdown clones to radiotherapy. These experiments suggest that autophagy inhibitors could target therapy-resistant PKP3 deficient tumors.

MicroRNAs: The key players regulating the crosstalk between Hippo and Wnt/ß-catenin pathways in breast cancer.

Breast Cancer has the highest burden in females worldwide and is predicted to increase by many folds with increasing lifestyle related risk factors, genetic mutations, and an aging population. The Hippo signalling and Wnt signalling pathways were identified as important signal transducers involved in maintaining organ development, tissue homeostasis, cell proliferation and apoptosis. microRNAs are short nucleotide sequences which act as regulatory components driving signal transductions in most cancers and can serve as both diagnostic and prognostic markers. Several reports have implicated that deregulated Hippo as well as Wnt signalling mediated by miRNAs together drive tumorigenesis, metastases and chemoresistance in breast cancer. Recent evidences on a crosstalk between Hippo and Wnt components elucidated how these pathways might be synchronized to have overlapping functions to promote tumorigenesis. Since miRNAs are demonstrated to target most of the components in both the pathways, in this review, we talk about the crosstalk between Hippo and Wnt signalling pathways and the potential microRNAs that might regulate the interplay between the two pathways in breast cancer, which has not been explored earlier.